Cell migration is fundamental to normal central nervous system (CNS) development and perturbations in this process have been implicated in the pathogenesis of many neurologic disorders including epilepsy, mental retardation and autism. Understanding the pathogenesis of these all to common disorders requires, among other processes, the elucidation of the molecular and cellular mechanisms governing neuronal migration. Two primary pathways of cell migration are recognized during cerebral cortical development, radial and non-radial. At least in rodents, radial cell migration, from the pallial ventricular zone out to the cortical plate, gives rise to the projection neurons of the cerebral cortex, whereas cortical interneurons must travel along non-radial pathways from the subpallial proliferative zones to arrive in the cortical plate. Over the past five years, supported by this grant, we have made significant contributions to our understanding of interneuron migration. Over the next two years we plan to extend these studies to more clearly define the mechanisms governing non-radial cell migration in mammals. One fundamental questions is how does the leading process respond to guidance cues to direct the migrating interneurons from the ganglionic eminence along their circuitous path and finally into the cerebral cortex. We have hypothesis that the leading process functions like a growth cone by dynamically regulating its cytoskeleton in response to long and shortrange cues. Herein we propose to define the cytoskeletal dynamics in the migrating leading processes and establish how they are regulated by guidance cues (aim 1) and determine how Lis1 effects leading process dynamics (aim 2). Together these data will establish the cellular mechanisms by which the leading process is able to lead the migrating interneuron, an integral component of normal brain development and one that is disrupted in many neurologic disorders.